The goal of this study is to determine the efficacy of the 1) ribociclib and everolimus to treat pediatric and young adult patients newly diagnosed with a high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (cell cycle, PI3K/mTOR) that these drugs target or 2) ribociclib and temozolomide to treat pediatric and young adult patients newly diagnosed with diffuse hemispheric glioma (DHG), H3G34-mutant.
The main question the study aims to answer is whether the combinations of ribociclib and everolimus or ribociclib and temozolomide can prolong the life of patients diagnosed with HGG/DIPG or DHG H3G34-mutant.
Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata C-D)
Stratum B: Patients with DIPG
Stratum C: Patients with primary thalamic, spinal cord, and/or secondary/radiation-related HGG.
Stratum D: Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received CSI.
Pregnant or Breast-Feeding Pregnant or breast-feeding women will not be entered on this study due to known potential risks of fetal and teratogenic adverse events as seen in animal/human studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use at least one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy
Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation.
Progesterone-only hormonal contraception associated with inhibition of ovulation.
Intra Uterine Device (IUD)
Parallel
Ribociclib
DrugRibociclib PO qd on days 1-21
Everolimus
DrugEverolimus PO qd on days 1-28
Temozolomide (TMZ)
DrugTemozolomide PO qd on days 1-5 for the first 13 cycles
Progression-Free Survival (PFS) in HGG (Part 2, Stratum A)
To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG by estimating the distribution of PFS compared to molecularly-stratified and matched historical controls.
Overall Survival (OS) in DIPG (Part 2, Stratum B)
To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with DIPG by estimating the distribution of OS compared to molecularly-stratified and matched historical controls.
Establish MTD and RP2D of ribociclib and everolimus (Part 2, Stratum D)
To identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and everolimus given to patients with metastatic HGG who have received craniospinal irradiation CSI.
Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0 (Part 1- initial feasibility study)
Identify the safe dose of ribociclib powder for oral solution (PfOS) formulation in combination with everolimus that is feasible in pediatric patients with newly-diagnosed HGG, including DIPG, with cell cycle and/or PI3K/mTOR pathway alterations. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0 in the first 6-12 patients enrolled
Overall Survival in HGG
Determine distribution of OS for pediatric and young adult patients newly-diagnosed with HGG which harbor cell cycle and/or PI3K/mTOR pathway alterations treated with post-RT ribociclib and everolimus.
Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0
Assess and further characterize the safety and toxicity of post-RT combination of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG, including DIPG. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0.
Evaluate Health-Related Quality of Life Outcomes
Evaluate health-related quality of life outcomes of pediatric and young adult patients newly-diagnosed with either 1) HGG, including DIPG, or 2) DHG, H3G34-mutant treated with combination of ribociclib and everolimus or ribociclib and temozolomide, by patient and/or parent reporting at key timepoints in therapy using the patient reported outcomes measurement information system (PROMIS) survey.
Overall Survival in DHG, H3G34-mutant
Determine distribution of OS for pediatric and young adult patients newly-diagnosed with DHG, H3G34-mutant treated with post-RT ribociclib and temozolomide.
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Nationwide Children's Hospital
Lead sponsor
Novartis
Collaborator
